Thermal Characterization of Cyclopropylacetylene, a Key Intermediate in the Manufacture of Sustiva

摘要

Cyclopropylacetylene (CPA) is used in multi-kilogram quantities in the synthesis of efavirenz (Sustiva), an antiretroviral non-nucleoside reverse transcriptase inhibitor used to treat HIV infections. Numerous literature citations exist for the preparation of CPA, but little information exists about process safety in the handling of this reagent. Systematic thermal characterization of CPA using the Accelerating Rate Calorimeter (ARC) was performed. Experimental parameters such as solution concentration, effect of thermal inertia, trace metal contamination and mode of thermoanalysis were evaluated. Data indicate strong decomposition behavior with a potential for a serious run-away event. Based on a plot of the self-heat rate versus temperature, a three-stage process is proposed for the thermal event. Mathematical deconvolution of the three stages can provide both kinetic and thermodynamic information for the thermal event. Based on this study, protective measures and proper vent sizing for vessels can be chosen thereby reducing the thermal hazards associated with the use of this material.